Hepatic disease is a world-wide common and frequently-happening disease. Liver damage is caused by invasion of extraneous factors such as virus, organisms, medications, physical and chemical factors, alcohol and the like. There are more than 280 million silent hepatitis B (HBV) carriers (HBsAg carriers) in the world and around 93 million in our country. About 30% of HBV carriers show clinical manifestation of liver damage. Hepatitis C virus (HCV) infection is a common infection which can lead to chronic hepatitis, hepatocirrhosis, hepatic failure and hepatocellular carcinoma, and at least 85% of the HCV infection cause chronic hepatitis. It is found by investigation that same as HBV, HCV's tissue infiltrating cell is primarily CD3+ and cytotoxic T cells (TCL) specifically attack target cell infected by HCV, causing hepatocellular damage.
At present, effective anti-HCV therapy is still limited to interferon therapy or its combined therapy with ribavirin, and vaccines which can effectively prevent HCV have not been developed. However, since about half of the patients treated with these known medications show remaining HCV inside their bodies, there is still a strong demand for alternative HCV medicaments. HCV is the only member of the Hepaciviruses of the Flaviviridae family. Bovine viral diarrhea virus (BVDV) is a virus of Flavivirus genus of the Flaviviridae family and has the same antigen as HCV. It's impossible to steadily culture HCV externally to date, but BVDV can easily grow in Madin Darby bovine kidney (MDBK) cell and its gene coding product can be easily obtained and thus is convenient for use in genomic research. BVDV AV69 (NADL) strain can cause pathological change in cells, so that the antiviral activity of a medicament could be assessed by using the rate of protection against pathological changes. Since the medicaments which can inhibit BVDV replication in cells could be used to treat HCV infection, BVDV has been used in HCV medicament screening extensively as a simulation strain of HCV.
Andrographolide is a diterpene lactone compound extracted from Andrographis paniculata (Burm.f.) Nees, is one of the major active components of Andrographis paniculata and is clinically used in the treatment of upper respiratory tract infection and bacillary dysentery and the like. In recent years, the investigation of use of andrographolide in anticancer, liver and gallbladder protection, antivirus and the like is continuously progressing. Andrographolide has excellent protective effect against several animal experimental liver damages. Qing Yao et al. found andrographolide had some protective effect against acute liver damage induced by cocaine, and the mechanism might relate to inhibition of lipid peroxidation and lowering the production of oxygen free radical in tissue. Visen P K [J Ethnopharmacol, 1993, 40(2), 131-136] and Handa S [Indian J Med Res., 1990, 92:284-292] both proved andrographolide had protective effect against liver damage induced by paracetamol, wherein Handa S's work also proved the protective effect against hepatotoxicity caused by galactosamine. Kapil A et al. [Biochem Pharmacol, 1993, 46(1):182-185] proved andrographolide, andrographoside and neoandrographolide had protective effect against hepatotoxicity caused by carbon tetrachloride and t-butyl peroxide. The study of Singha P et al. [J Ethnopharmacol. 2007; 111(1):13-21] showed andrographolide had some protective effects against kidney and liver damage caused by ethanol in mice. The study of Roy D N et al. [Toxicol Appl Pharmacol. 2011; 250(1): 54-68] proved combination of andrographolide and D-green enzyme amine in treatment of copper poison had better effect than single use of D-green enzyme amine in treatment of anti-fibrillation and necrocytosis. Guang Ning et al. disclosed in their application CN201010266185.2 the use of andrographolide in preparation of a medicament for treatment of acute liver damage, and that andrographolide can significantly suppress liver damage and liver cell apoptosis induced by concanavalin A and suppress the inflammation reaction of liver, and thus, it can be used to treat liver damage induced by concanavalin A.
As revealed by experiments, andrographolide and its derivatives had excellent prospective for use in anti-flavivirus, anti-pestivirus or anti-hepatitis C virus applications (CN: 200580046253.1) and anti-SARS virus applications (CN: 03129127.9). Combination of ingredients of herba andrographitis with other plants or the ingredients thereof has antiviral activity. (U.S. Pat. No. 5,833,994) disclosed the combination of andrographolide with an arene ligand in treatment of virus infection. Andrographolide succinic acid monoester inhibited HIV by interrupting its binding with cells and by interfering with its replication cycle till subsequent stage of its binding with cells. Methanol extract of Andrographis paniculata could inhibit HIV-1 in vitro replication by inhibiting c-Mos.
The inventors have obtained a lot of structurally novel compounds in previous studies (CN1978437; CN100999520; CN100999535; CN101003527), for which compounds patent protections on their anticancer, anti-inflammatory and anti-HBV applications are sought for. Then, activity tests of the anti-HCV and hepatoprotective effects of 15-benzylidene-14-deoxy-11, 12-dehydroandrographolide derivatives and the 3, 19-ester thereof are further conducted.